Prophylaxis and treatment of cardiac disorders

ABSTRACT

3,4,5-Trialkoxybenzoyl alkanoic acids and their pharmaceutically-acceptable salts for prophylaxis and treatment of cardiac disorders.

ilited States Patent i191 Camila [111 3,857,949 [4 Dec. 31, 1974PROPHYILAXIS AND TREATMENT OF CARDIAC DISORDERS [75] Inventor: AldoGarzia, Lodi, Italy [73] Assignee: lnstituto Chemioterapico ItalianoS.p.A., Milan, Italy 22 Filed: Feb. 16, 1972 21 Appl. No.: 226,985

Related US. Application Data [62] Division of Ser. No. 50,325, June 26,1970.

[52] US. Cl. 424/317 [51] Int. Cl A61k 27/00 [58] Field of Search424/317 [56] References Cited OTHER PUBLICATIONS Koo; 1., Am. Chem.Soc., 75, 720-723, 1953. Haworth; Chem. Abstracts, Vol. 43, 3403.

Primary ExamineF-Stanley J. Friedman Attorriey, Agent, or Firm-M0rton,Bernard, B'rown, Roberts & Sutherland [5 7 ABSTRACT 8 Claims, NoDrawings PROPHYLAXIS AND TREATMENT OF CARDIAC DISORDERS This is adivision of application Ser. No. 50,325 filed June 26, 1970.

BACKGROUND OF THE INVENTION This invention relates to a method ofprophylaxis and treatment of cardiac disorders. In a particular aspect,it relates to a method of treating ischemic cardiopathy prior to orfollowing a cardiac infarction, disorders of rhythm, and disorders ofstimulus transmission by the administration of an alkanoic acidderivative.

The prevention and treatment of cardiac disorders, such as ischemia,thrombosis, cardiac infarction and disorders of rhythm and stimulustransmission, is a serious problem. Many studies have been conducted inan effort to ascertain the underlying causes and to develop a suitablemethod of preventing or treating these serious problems, particularlycardiac insufficiency and cardiac infarction. The pharmacologicalmethods which have been proposed for preventing cardiac infarctioninclude lowering of blood cholesterol levels, relaxation of the arteriesand administration of antico-' agulants. Ventricular fibrillation is ahighly dangerous condition which is treated by electric shockadministered to the heart muscle, and other rhythm and transmissiondisorders respond to installation of the pacemaker device.

While the use of these methods has greatly improved the prognosis ofcardiac patients, the problem of cardiac disorders generally stillremains a severe one and' in particular the problems caused byinfarction are still grave.

SUMMARY OF THE lNVENTION salts of the compounds of this invention arepreferred.

5 pared generally by the method described in an article It is an objectof this invention to provide a method of prophylaxis and treatment ofcardiac disorders.

It is another object of this invention to provide novel pharmaceuticalcompositions suitable for the prophylaxis and treatment of cardiacdisorders.

Another object of this invention is to provide a method of prophylaxisand prevention of ischemic cardiopathy, cardiac infarction and disordersof rhythm and stimulus transmission by the administration of derivativesof benzoylalkanoic acids.

Other objects of this invention will be readily apparent to thoseskilled in 'the art from the disclosure herein.

It has been discovered that administration of compounds corresponding tothe following formula where each of R maria-airs methyl, ethyl or propyland A is a saturated aliphatic hydrocarbon radical containing 3-8 carbonatoms substituted with one carboxylic acid group, or theirpharmaceutically-acceptable salts, is effective in the prophylaxis andtreatment of cardiac disorders such as cardiac ischemia and infarction,disorders of rhythm and disorders of stimulus transmission. The compoundis administered at a dosage of 2-8g per day per average 60-70 kg.individual. When administration is by intravenous or intraperitonealinjection, soluble, pharmaceutically acceptable appearing in The Journalof the American Chemical Society, Volume LXXV, January-March l953, byJohn Koo, at pages 720-723.

The article specifically describes the preparation of'y-(3,4,5-trimethoxybenzoyl)-butyric acid by the reaction of ethyl3,4,5-trimethoxybenzoylacetate with methyl B-bromopropionate in thepresence of sodium in absolute ethanol at low temperature, i.e. 0C,followed by hydrolysis of the crude ester with sulfuric acid.

According to the method of the present invention, compoundscorresponding to the formula given hereinbefore are administered for thetreatment of cardiac ischemia, either prior to or following a cardiacinfarction, disorders of the rhythm whether related to the infarction ornot, and disorders of stimulus transmission. Administration of thesecompounds is an effective prophylaxis in cases of an impending cardiacinfarction and an effective treatment after infarction has occurred.According to one embodiment of the present invention, the method isemployed in veterinary medicine, principally in the treatment ofhousehold pets, .especially dogs, where cardiac problems are frequentlyencountered.

Cardiac infarction frequently occurs without prior symptoms or beforethe patient has sought treatment for the relief of symptoms. Howeverphysicians are frequently able to detect symptoms of an approachingcrisis and the administration of the compounds of this invention can bestarted promptly to obtain prophylactic effects.

The products of the present invention are of a loworder of toxicity andno side effects are observed in clinical trails. Pharmacological studiesindicate that the principal effect of the compounds of the invention ison the heart. The only observed effect on the circulatory system is anincrease in the static blood pressure with no significant change in.mean arterial pressure.

The dosage in which the compounds of the present invention can be givencan'vary widely within rather broad limits. Good results have beenobtained with as little as 25v mg/kg/day and as much as 500 mg/kg/day.In human clinical cases, all of the disorders cited above generallyrespond to a dosage of 2-8 grams per day per person, preferably about 6grams per day. This dosage is intended for an average 60-70 kgindividual equivalent to a dosage generally within the range of about25-200 mg/kg/day. A dosage in the range of about 40-100 mg/kg/day ispreferred. The treatment can consist of a single daily dose, or theabove dosages can be given fractionally at periodic intervals. A singledaily dose is generally preferred for a treatment of cardiac infarctionand associated disorders but for prophylaxis, smaller periodic doses,e.g. a 500 mg dose, 6 times daily, is preferred.

Administration of the compounds of this invention can be oral,subcutaneous, intravenous or intraperitoneal. When the compounds of thepresent invention are by subcutaneous, intraperitoneal or intravenous injection, they are administered as their water-soluble neutralsalts. Anysoluble, pharmaceutically-acceptable salt is suitable and the sodium andpotassium salts are preferred. The sodium salt is particularlypreferred. For oral administration the compounds are preferablyadministered as the free acids but they can also bepharmaceutically-acceptable salts, eg as the ammonium, sodium,potassium, magnesium or calcium salt. According to one suitable method,the free acids can be administered mixed with a molar equivalent ofsodium or potassium bicarbonate. 1n the examples, the compounds wereadministered intraperitoneally as the sodium salt because of its ease ofhandling as an aqueous solution, but the weights given are for the freeacid. When administered orally, the compounds are convenientlyadministered as tablets containing 500 mg with a suitable binder, manyof which are known.

Suitable tablets for human or animal use can conveniently be preparedcontaining 50-500 mg of the com pounds of the present invention, eitheras the free acid or as a pharmaceutically-acceptable salt thereof.Tablets containing as little as 50 mg are suitable for oraladministration, especially for infants and small children, and inveterinary medicine, for small animals. Tablets containing less than50mg can be prepared, and in special cases may be useful, but generallya dose smaller than 50 mg is too small to be practical because in theaverage patient the number of tablets required per day would beexcessively high for convenience. Tablets containing more than 500intravenously. Electrocardiograms are taken and the extent of thearrhythmia also be prepared, but large tablets are difficult for mostpatients to swallow.

EXAMPLE l In the following example, the experimental procedure describedat page 722 of the article in Journal of the American Chemical Society,Volume LXXV, January-March 1953, was duplicated.

To a solution of 3.5 g. of sodium in 250 ml. of absolute ethanol wasadded, at 40, 28.2 g. of .ethyl 3,4,5-

trimethoxybenzoylacetate. The mixture was stirred for 10 minutes, thenmaintained below during the dropwise addition with continued stirring of2.17 g. of methyl B-bromopropionate. An interval of an hour was allowedto elapse between the addition of the first 0.17 g. portion of the bromoester and of the remainder. The suspension was stirred for an additional3 to 4 hours at 5l0, allowed to stand at overnight, diluted withice-water and acidified with dilute hydrochloric acid. Extraction withether followed by washing, drying and evaporating yielded 40 g. of apale yellow oil, which was too unstable for purification.

The crude ester was refluxed with 250 ml. of sulfuric acid for 45 hours.The mixture was chilled and the partly gummy crude acid treated with 200ml. of 5% sodium hydroxide. Neutral material was removed by filtrationand the filtrate acidified to yield 23 g. (81%) of almost colorlesscrystalline material. Recrystallization from water gave colorlessplates, m.p. ll8l20 (reported l2012l).

acid having the structure EXAMPLE 2 The effect of the compound preparedaccording to the procedure of Example 1 on the heart is determined inrats by intravenous injection of 1 unit per kilogram of vasopressin(Pitressin, marketed by Parke, Davis Co.), an antidiuretic pituitaryhormone. As is known, the administration of vasopressin results invariations of the voltage and the morphology, or shape, of the T- wave.It also causes arrhythmia and produces ischemia of the myocardium. 1t isdetermined that these electrocardiographic alterations normally producedby the administration of Pitressin are prevented by the administrationof the compound of Example 1.

EXAMPLE 3 EXAMPLE 4 y-(3,4,5-triethoxybenzoyl)-a-ispropyl propionic acidis prepared in accordance with the procedure of Example 1 except that3,4,5-triethoxybenzoylacetate and methyl-a-bromo isovalerate areemployed.

EXAMPLE 5 e-(3,4,S-triprOpOXybenZoyl a-dimethyl valeric acid is preparedin accordance with the procedure of Example 1 except that3,4,5-tripropoxybenzoylacetate and methyl-a-dimethyl-S-bromobutyrate areemployed.

EXAMPLE 6 y-(3,5-dimethoxy-4-ethoxybenzoyl)-a-isopentyl pro- -pionicacid is prepared in accordance with the procedure of Example 1 exceptthat 3,5-dimethoxy-4- ethoxybenzoyl acetate and methyl-a-bromoisoenanthate are employed.

EXAMPLE 7 2 ;-(3,4,5-trimethoxybenzoyl)-a-isopropyl caproic acid isprepared in accordance with the procedure of Example 1 except thatmethyl-S-bromo-a-isopropyl valerate is employed.

EXAMPLE 8 A pharmaceutical composition in tablet form was prepared bymixing 500 mg of the compound of Example l with'50 mg of corn starch and50 mg of sucrose. This mixture was compressed in a tableting machine tomake a durable tablet. lt is suitable for oral administration to humansor other animals suffering from cardiac disorders. It is particularlysuitable for prophylaxis of a suspected impending occlusion resulting inan infarction.

The above examples are representative. For example, the3,4,5-trialkoxybenzoic acids are well known to the art. See, forexample, US. Pat. Nos. 3,234,276; 1

3,364,249 and 3,485,865.

Caproic acid is available in commercial quantity and the commercialgrade materials are suitable for preparing the products of thisinvention. The corresponding valeric, butyric, heptanoic, octanoic andnonanoic acids together with their isomers are prepared by knownmethods.

The recommended dosage during the first 24 hours following infarction isas follows:

2-4 grams by phlebocylsis; l-2 ampoules (each ampoule containing 2,000mg of the sodium salt of the compound of Example-l dissolved insufficient sterilized distilled water to make cc) dissolved in 400-600cc of saline solution.

2-4 grams by intravenous administration; 2-4 ampoules divided into 2-4administrations (each ampoule containing 1,000 mg of the sodium salt ofthe compound of Example 1 dissolved in sufficient sterilized distilledwater to make 10 cc).

2 grams by intramuscular administration; 8 ampoules divided into 4administrations (each ampoule contain ing 250 mg of the sodium salt ofthe compound of Example l and sufficient sterilized distilled water tomake 3 cc).

4-6 grams by oral administration; 8-12 tablets (each tablet containing500 mg of the sodium salt of the compound of Example 1 and sufficientexcipient to make one tablet).

4-6 grams by oral administration; 8-12 ampoules (each ampoule containingone or two grams of the sodium salt of the compound of Example 1 insufficient sterilized distilled water to make 10 cc).

In the third or fourth day after start of therapy, the dosage can bereduced to half the above amounts. The therapy should not be interruptedbefore the 3rd week after heart infarction has occurred.

Both in the attack phrase and in the maintenance stage the therapy canbe carried out using one or more of the different forms ofadministration.

I claim:

1. A method of prophylaxis or treatment of ischemic cardiac disorderscomprising pharmacologically administering to an animal a compoundrepresented by the formula 6 mg/kg/day.

2. The method of claim 1 where R, R and R are methyl andA is (CH2)3COOH.

3. The method of claim 2 wherein said compound is administered at adosage within the range of about 25-200 mg/kg/day.

4. A method of claim 1 wherein the animal treated for ischemic cardiacdisorders or for prophylactic effects is a dog.

5. The method of claim 1 wherein the ischemic cardiac disorder resultsfrom myocardial thrombosis.

6. A method of prophylaxis for treatment of cardiac ischemia,infarction, disorders of rhythm or disorders of stimulus transmission inanimals comprising administering to the animal a compound represented bythe formula wherein each of R R and R is methyl, ethyl or propyl and Ais a saturated aliphatic hydrocarbon radical containing 3 8 carbon atomssubstituted with one carboxylic acid group, or apharmaceutically-acceptable salt thereof, at a dosage within the rangeof 25-500 mg/kg/day.

7. A method of prophylaxis and for treatment of cardiac ischemiacomprising pharmacologically administering to an animaly-(3,4,5-trimethoxybenzoyl)- butyric acid or apharmaceutically-acceptable salt thereof selected from the groupconsisting of the ammonium, sodium, potassium. magnesium. and calciumsalts, at a dosage within the range of 25 500 mg/kg/day for effectiveprophylaxis or effective treatment of cardiac ischemia.

8. A pharmaceutical composition in the form of a tablet or sterileampoule useful for prophylaxis or treatment of ischemic cardiacdisorders in animals comprising a binder and a dosage amount of acompound of the formula wherein each of R R and R is methyl, ethyl orpropyl and A is a saturated aliphatic hydrocarbon radical containing 3-8carbon atoms substituted with one carboxylic acid group, or apharmaceutically-acceptable salt thereof, for effective prophylaxis oreffective treatment of ischemic cardiac disorders upon administra-UNITED sTATEs PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 857,949 Dated December 31, 1974 Inventor(s) ALDO GARZIA It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 2, line 39, "trails" should be trials-- Column 3, lines 27 and28, "intravenously arrhythmia" should be deleted and -mg can shouldappear.

Column 4, line 23, after "nously." should appear -Eleotrocardiograms aretaken and the extent of the.

Column 4, line 30, "ispropyl" should appear as -isopropyl-.

Signed and sealed this 24th day of June 1975.

(SEAL) Attest:

C. Z'ZARSHALL DANN RUTH C. ZZASQI?! Commissioner of Patents AttestingOfficer and Trademarks FORM PO-lOSO (10-69) USCOMMQDC 50375. :59

u.s GOViRNMENT PRINTING OFFICE: 8 930

1. A METHOD OF PROPHYLAXIS OR TREATMENT OF ISCHEMIC CARDIAC DISORDERSCOMPRISING PHARMACOLOGICALLY ADMINISTERING TO AN ANIMAL A COMPOUNDREPRESENTED BY THE FORMULA
 2. The method of claim 1 where R1, R2 and R3are methyl and A is -(CH2)3COOH.
 3. The method of claim 2 wherein saidcompound is administered at a dosage within the range of abouT 25-200mg/kg/day.
 4. A method of claim 1 wherein the animal treated forischemic cardiac disorders or for prophylactic effects is a dog.
 5. Themethod of claim 1 wherein the ischemic cardiac disorder results frommyocardial thrombosis.
 6. A method of prophylaxis for treatment ofcardiac ischemia, infarction, disorders of rhythm or disorders ofstimulus transmission in animals comprising administering to the animala compound represented by the formula
 7. A method of prophylaxis and fortreatment of cardiac ischemia comprising pharmacologically administeringto an animal gamma -(3,4,5-trimethoxybenzoyl)-butyric acid or apharmaceutically-acceptable salt thereof selected from the groupconsisting of the ammonium, sodium, potassium, magnesium, and calciumsalts, at a dosage within the range of 25 - 500 mg/kg/day for effectiveprophylaxis or effective treatment of cardiac ischemia.
 8. Apharmaceutical composition in the form of a tablet or sterile ampouleuseful for prophylaxis or treatment of ischemic cardiac disorders inanimals comprising a binder and a dosage amount of a compound of theformula